Nitric Oxide Can Alter Brain Function

November 27, 2008— Research from the Medical
Research Council (MRC) Toxicology Unit at the University of Leicester
shows that nitric oxide (NO) can change the computational ability of
the brain. This finding has implications for the treatment of
neurodegenerative diseases such as Alzheimer's Disease and our
understanding of brain function more generally.

The research is led by Professor Ian Forsythe and is reported in the journal Neuron on 26th November.

Professor Forsythe, of the MRC Toxicology Unit, explains: "It is
well known that nerve cells communicate via the synapse – the site at
which chemical messengers (neurotransmitters such as acetylcholine or
glutamate) are packaged and then released under tight control to
influence their neighbours.

"Nitric oxide is a chemical messenger which cannot be stored and can
rapidly diffuse across cell membranes to act at remote sites (in
contrast to conventional neurotransmitters which cannot pass across
cell membranes).

"It is broadly localized in the central nervous system, where it
influences synaptic transmission and contributes to learning and memory
mechanisms. However, because it is normally released in such minute
quantities and is so labile, it is very difficult to study.

"We have exploited an in vitro preparation of a giant synapse
-called the calyx of Held, developed here at the University of
Leicester in the 1990s- and its target in the auditory pathway to
explore nitric oxide signalling in the brain.

"We show that NO is made in response to incoming synaptic activity
(activity generated by sound received by the ear) and that it acts to
suppress a key potassium ion-channel (Kv3). Normally these ion-channels
keep electrical potentials very short-lived, but nitric oxide shifts
their activity, slowing the electrical potentials and reducing
information passage along the pathway, acting as a form of gain control.

"Surprisingly, the whole population of neurons were affected, even
those neurons which had no active synaptic inputs, so indicating that
nitric oxide is a 'volume transmitter' passing information between
cells without the need for a synapse. Such a function is ideal for
tuning neuronal populations to global activity. On the other hand, too
much nitric oxide is extremely toxic and will cause death of nerve
cells; so within the kernel of this important signaling mechanism are
the potential seeds for neurodegeneration, which if left unchecked
contribute to the pathologies of stroke and dementias."

In the future Professor Forsythe's research group will be trying to
understand how these signalling mechanisms are applicable elsewhere in
the brain and will investigate how aberrant signalling contributes to
neurodegenerative disease processes such as in Alzheimer's disease.